Running on mixed fuel‐dual agonistic approach of GLP‐1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non‐human primates

Elvert, Ralf; Herling, Andreas W.; Bossart, Martin; Weiß, Tilo; Zhang, Baohong; Wenski, Pierre; Wandschneider, Jörn; Kleutsch, Sabrina; Butty, Uwe; Kannt, Aimo; Wagner, Michael R.; Haack, Torsten; Evers, Andreas; Dudda, Angela; Lorenz, Martin; Keil, Stefanie; Larsen, Philip J.

doi:10.1111/dom.13212

Cited by 34 publications

(34 citation statements)

References 45 publications

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“…An experimentally-increased amount of glycogen in the liver by itself induced hepatic insulin resistance and inhibited new glycogen synthesis in healthy dogs [ 38 ]. Interestingly, novel classes of glucose-lowering drugs, SGLT2 inhibitors and dual GLP1/glucagon agonists, are also known to reduce liver glycogen storage [ 39 – 41 ]. In addition, clenbuterol could also affect insulin sensitivity through a reduction in inflammation, since these two conditions are closely associated (reviewed in [ 42 , 43 ]).…”

Section: Discussionmentioning

confidence: 99%

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

et al. 2020

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Aims/hypothesis Chronic stimulation of β 2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of β 2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of β 2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg −1 day −1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%, p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 ± 0.31%/min in comparison with 0.15 ± 0.36%/min in control mice, p < 0.05) and drastically reduced hepatic steatosis (by 40%, p < 0.01) and glycogen (by 23%, p < 0.05). Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and Anastasia Kalinovich and Nodi Dehvari contributed equally to this study.

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Section: Discussionmentioning

confidence: 99%

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

et al. 2020

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“…The dual GLP‐1/GCG RA peptide 15 was used as comparator. [ 21 ] To guide dose selection, single dose s.c. administration PK studies in monkeys were performed. Peptide 12 showed a half‐life of 4.7 h, whereas 15 showed a longer half‐life of 7.5 h and a higher exposure.…”

Section: Figurementioning

confidence: 99%

Multiparameter Peptide Optimization toward Stable Triple Agonists for the Treatment of Diabetes and Obesity

Evers

Pfeiffer-Marek

Bossart

et al. 2020

Advanced Therapeutics

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Historically, peptide optimization has mainly focused on pharmacological activity. Physicochemical properties have often been evaluated late in discovery, potentially providing molecules with suboptimal stability properties. Often, such issues cannot be overcome by formulation approaches but need additional optimization cycles for a redesign of the peptide. Here, early rational multiparameter optimization of exendin‐4 based agonists is described toward i) a balanced triple activity profile at the glucagon‐like peptide 1, glucagon, and gastric inhibitory polypeptide receptors for the treatment of diabetes and obesity and in parallel ii) robust physicochemical properties for 1‐daily subcutaneous application in a multiple‐dose pen device. In depth evaluation of an optimized candidate shows an excellent profile with respect to its physicochemical properties and pharmacokinetic/pharmacodynamic (PD) behavior in minipigs and monkeys.

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“…SAR425899 was developed for the treatment of patients with T2D and obesity 11 – 14 aiming to lower glucose at least similar to marketed GLP-1 agonists, but with superior weight loss over GLP-1 receptor mono-agonists. Preclinical studies with SAR425899 clearly demonstrated dual receptor agonism in vitro and in preclinical in vivo studies, with a higher potency for the GLP1R than for the glucagon receptor in order to counterbalance the GCGR mediated increase of blood glucose levels through GLP-1 agonism 11 – 13 . Because read outs for GCGR specific binding were missing, data from early clinical studies were unable to confirm the dual agonism of SAR425899 in humans 14 .…”

Section: Introductionmentioning

confidence: 99%

Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes

Eriksson

Haack

Hijazi

et al. 2020

Sci Rep

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Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [68Ga]Ga-DO3A-Tuna-2 and [68Ga]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 ± 14.4% (SD) in N = 5 patients and a GLP1R occupancy of 49.9 ± 13.3%. Fasting Plasma Glucose levels (− 3.30 ± 1.14 mmol/L) and body weight (− 3.87 ± 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.

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Running on mixed fuel‐dual agonistic approach of GLP‐1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non‐human primates

Cited by 34 publications

References 45 publications

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

Multiparameter Peptide Optimization toward Stable Triple Agonists for the Treatment of Diabetes and Obesity

Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes

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